DESCRIPTION: Smoking is the leading cause of preventable deaths. Although cigarette smoking increases the risk of several chronic diseases, nearly half of smoking related mortality could be linked to cardiovascular deaths. Therefore, regulation of cigarettes and other tobacco products could significant lower the global burden of cardiovascular disease (CVD). The Family Smoking Prevention and Tobacco Control Act gives the FDA the authority to regulate the manufacturing, marketing and distribution of tobacco products to protect public health. However, to set standards for tobacco products, it is important to know how cardiovascular effects of new and emerging tobacco products could be measured and which components of tobacco products induce cardiovascular injury. Because CVD is a chronic disease that develops over several years, biomarkers of tobacco-induced cardiovascular injury are urgently needed to assess CVD risk in a time-frame sufficient for product evaluation. Moreover, to relate biomarkers of injury with exposure to specific harmful and potentially harmful (HPHC) tobacco constituents, it is essential to identify biomarkers that reflect exposure to specific constituents of tobacco products. Elucidation of the relationship between biomarker of exposure and biomarkers of injury will enable comparisons between the toxicities of different tobacco products and inform the design of future human studies for evaluating the cardiovascular effects of tobacco product use. Accordingly, the overall goal of our project is to identify biomarkers of exposure to tobacco products and to relate them to atherosclerosis, the underlying cause of several cardiovascular diseases. To accomplish this goal we will examine tobacco-induced injury in apoE-null mice and apoE-null rats. We will expose animals to varying intensities of tobacco smoke and smokeless tobacco, we will identify urinary metabolites of exposure-derived aldehydes and determine how they relate to the extent and duration of exposure as well as to atherosclerotic lesion formation and lesion stability and how the relationship between the biomarkers of injury and biomarkers of exposure is affected by gender and the species and duration of exposure. In these experiments, we will identify specific indices of atherosclerosis and thrombosis and how these biomarkers of injury are related to the biomarkers of exposure. To delineate the contribution of HPHCs, we will identify which constituents of tobacco and tobacco smoke contribute to atherogenesis, we will examine atherogenesis in mice exposed to individual constituents of exposure - nicotine, acrolein and crotonaldehyde, and determine how removal of these constituents affects atherosclerosis due to tobacco smoke and whether increases in the extent of exposure to these aldehydes and related reactive chemicals exacerbate atherosclerosis. Successful completion of this project will lead to the development of validated animal models to establish standard toxicity changes and the discovery of novel biomarkers of cardiovascular injury that can be associated with measures of tobacco exposure. The findings of this project will provide new information regarding the contribution of reactive aldehydes such as acrolein and crotonaldehyde to the cardiovascular toxicity of cigarette smoke and smokeless tobacco. These findings will be useful in evaluating the contribution of HPHCs to tobacco product toxicity in humans; assessing the extent of harm reduction in PREPs and in developing policies for regulating HPHCs in smokeless tobacco, cigarettes and emerging tobacco products. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page